Adducts of 12-hydroxy-5,7,9(11)-pregnatrien-20-ones



United States Patent ADDUCTS 0F 12-HYDROXY-5,7,9(11)-PREGNATRlEN-20-ONES Robert H. Levin, Kalamazoo Township, KalamazooCounty, A Vern McIntosh, Jr., Kalamazoo, and George B. Spero, KalamazooTownship, Kalamazoo County, Mich., assignors to The Upjohn Company,Kalamazoo, Mich., a corporation of Michigan No Drawing. Application May22, 1953, Serial No. 356,893

9 Claims. (Cl. 260-23955) The present invention relates to adducts of12-hydroxy- 5,7,9(11)-pregnatrien-20-ones with certain acids,anhydrides, imides and esters of a,;8-unsaturated dicarboxylic acids,particularly with maleic anhydride, maleimide and esters of maleicacids, and to processes for their productron.

This application is a continuation-in-part of our copending applicationSerial No. 184,702, filed September 13, 1950, now U. S. Patent2,623,043, issued December .23, 1952, and of our copending applicationSerial No.

228,132, filed May 24, 1951, now abandoned, to which reference is madealso for the preparation of the starting compounds referred to in thisspecification.

The adducts of 12-hydroxy-5,7,9(11)-pregnatrien-20- ones which are thepreferred embodiment of this invention are represented by the followingformula:

CH: CH3

in which the Y in the 3 position of the steroid nucleus is hydrogen oran acyl radical of an organic carboxylic acid, especially thosealiphatic hydrocarbon carboxylic acids containing from one to eightcarbon atoms, inclusive, per molecule, and A is the adduct radical of ana,,8-unsaturated carbonyl compound of the group consisting of maleicacid, maleic anhydride, maleimide and dialkyl maleates containing fromone to eight carbon atoms, inclusive, in each alkyl radical.

The principal object of the present invention is to provide novelcompounds which are useful in the preparation of steroid compoundscontaining an oxygen atom attached to carbon atom eleven of the steroidnucleus. Another object of the present invention is to provide a processfor the production of these new compounds. Other objects and advantagesof the invention, some of which are referred to hereinafter, will beapparent to those skilled in the art to which the invention pertains.

The compounds of the present invention are useful in the preparation ofphysiologically active steroid compounds which possess an oxygen atom inposition 11 or 12. For example, heating a SB-acyloxy-lZ-hydroxy-5,7,9(11) pregnatrien 20 one or 313,12 dihydroxyogy, section I, volumeIV, 1943, A. W. T. Franks Pub- "ice lishing Company, Montreal, page 603;Hoehn and Mason, J. Am. Chem. Soc. 60, 1702 (1938); Reichstein et al.,Helv. Chim. Acta 23, 747 (1940)] which has anesthetic and luteoidproperties (Selye reference). When pregnane-3,12,20-trione is reactedwith sodium borohydride, the 3-keto and 12-keto groups are reduced.Treatment of the thus-obtained 3a,1Z-dihydroxypregnan-ZO-one with aceticanhydride yields the 3a-acetate and oxidation of this compound withchromic acid produces 3a-acetoxypregnane-12,20-dione which was convertedby Gallagher (U. S. Patent 2,447,325, columns 1 and 2) into3a-hydroxypregnane-l1,20-dione, which can be converted to cortisone bythe method of Kritchevsky, Garmaise and Gallagher, J. Am. Chem. Soc. 74,483 (1952).

Compounds of the present invention which are of particular interest arethose compounds conforming to the foregoing general formula and in whichYO represents hydroxyl or an acyloxy radical resulting from theesterification of the hydroxyl group of the steroid with a carboxylicacid containing up to and including eight carbon atoms. Such acidsinclude formic, acetic, propionic, butyric, valeric, hexanoic,heptanoic, octanoic, succinic, glutaric, cyclopentanoic, cyclohexanoic,benzoic, toluic, and the like; the lower aliphatic acids of this groupare preferred embodiments of the invention. The acids may containsubstituents, such as halogen, alkyl and methoxy radicals which arenon-reactive with the reagents used in the methods described herein forthe preparation of the compounds of the invention. The adduct bridge (A)that is represented between the 5 and 8 positions of the steroid nucleusof these compounds may be represented by the graphic formulae:

and

00R OOR the first of which represents that derived from maleic anhydrideand maleimide (in which Z represents an oxygen (--O--) or an imido (NH)radical) while the second represents that derived from maleic acid andits esters. In this second formula R- represents hydrogen or an alkylradical. Such alkyl radicals (R) include the methyl, ethyl, propyl,isopropyl, butyl, isobutyl, lauryl, heptyl, octyl, cyclopentyl,cyclohexyl, benzyl and similar radicals, which may contain substituentssuch as halogen, methoxy and hydroxyl radicals, which are non-reactivewith the reagents used in the methods described herein for theirpreparation. While adducts of esters of maleic acids are describedherein with particular reference to those of dimethyl maleate, thepreferred embodiment of R in the foregoing second formula is alower-alkyl radical containing from one to eight carbon atoms,inclusive.

The compounds of the present invention are usually colorless crystallinesolids. Those which are adducts formed from mil-unsaturated acids andanhydrides are readily convertible to diester adducts by esterificationwith reagents such as diazoalkanes in accordance with the methoddescribed by Wilds et al. in J. Org. Chem. 13, 763 (1948). The adductsof dicarboxylic acids may be converted to adducts of the correspondingdicarboxylic acid anhydrides by heat. The adducts of acid anhydrides maybe converted to those of the corresponding acid by hydration with water.

The starting compounds from which the compounds of the present inventionare prepared are adducts of 3/3- (hydroxy or acyloxy)-12-(brom0 oracyloxy)-5,7,9(11)- in which A and Y have the significance hereinbeforespecified and X is bromine or an acyloxy radical which results from theesterification of the IZ-hydroxyl group of the steroid, with acarboxylic acid containing up to and including eight carbon atoms, thesame as the acyl radicals included in the designation YO. Thepreparation of these compounds, which is described in detail in ourcopending application Serial No. 184,702, filed September 13, 1950, nowU. S. Patent 2,623,043, issued December 23, 1952, and in our copendingapplication Serial No. 228,131, filed May 24, 1951, now abandoned,consists essentially of the following (alternative procedures are alsodescribed in our said copending application):

(1) Dehydroergostero-l is converted to an adduct with maleic anhydrideor the desired equivalent of maleic anhydride lH. Honigmann, Annalen308, 89-98 (1934)].

(2) The adduct of dehydroergosterol is esterified by reaction, forexample, with benzoyl chloride, acetyl chloride or formic acid.

(3) The resulting adduct of the 3fl-acyloxydehydroergosterol is ozonizedand then reduced in acid solution with zinc dust to obtain a3fl-acyloxybisnor-5,7,9(11)- cholatrien-22-al. Serial No. 111,100, filedAugust 18, 1949, now U. S. Patent 2,620,337, issued December 2, 1952,for details).

(4) An enol ester of the resulting 3fl-acyloxybisnor-5,7,9(11)cholatrien-22-al is prepared and ozonized to the adduct of a3;3-acyloxy-5,7,9(11)-pregnatrien-20- one.

(5) The resulting adduct of the 3B-acyloxy-5,7,9(1l)- pregnatrien-ZO-oneis reacted with N-bromosuccinimide or bromine to produce an adduct of a3fi-acyloxy-12- bromo-5,7,9(11)-pregnatrien-20-one.

(6) From the adduct of the 3fl-acyloxy-12-bromo-5,7,9(l1)-pregnatrien-20-one, the adduct of the 35,12-diacyloxy-5,7,9(l1)-pregnatrien-20one, if this compound rather than the12-bromo steroid adduct is desired as the starting compound, can beprepared by reaction of the 12-bromo steroid adduct with a metal salt ofan esterifying acid or withan esterifying acid and zinc metal, asdescribed in our copending application Serial No. 228,131, filed May-24, 1951, now abandoned, and in Preparations 1 and 2 hereinafter,

In accordance with one of the processes of our invention, the adducts of12-bromo-3B-(hydroxy or acyloxy)- 5,7,9(11)-pregnatrien-20-ones areconverted to the desired l2-hydroxy-3 3-(hydroxy oracyloxy)-pregnatrien- -one by reaction with silver nitrate. The 12-bromosteroid adduct is dissolved in an organic solvent, for example, acetone,dioxane, or the like, and the silver nitrate in aqueous solution isadded thereto with stirring. Temperatures of from approximately zero toapproximately fifty degrees centigrade are suitable, with roomtemperatures being preferred. At the end of the reaction period, usuallyabout onehour the precipitated silver bromide is removed by filtrationand the 12-hydroxy-3 (hydroxy or acyloxy)-5,7,9(l1)-pregnatrien-20-oneadduct is precipitated by addition of water. The product may berecrystallized from an organic solvent to yield a more highly purifiedproduct, if desired. This process is illustrated in Examples 1 and 2hereinafter.

In accordance with another of the processes of our invention, theadducts. of 12-acyloxy-3fl-(hydroxy or acyloxy) -5,7,9(1l)pregnatrien-20-ones are converted to the desired 35,12-dihydroxy-5 ,7 ,91 1 )-pregnatrien-20 one by saponification with a base. Such, processesare illustrated in Examples 3, 5, and 6 hereinafter. In such processes,the adduct, if it is an anhydride or ester adduct, is generallyhydrolyzed to the acid adduct; the acid ad- (See application of RobertH. Levin,

duct may be restored to the anhydride adduct by heating at asubatmospheric pressure, as illustrated in Example 7 hereinafter. Thehydrolysis of the monoacyloxy (l2- acyloxy) steroids is generallyeffected with approximately three molecular equivalents of sodiumhydroxide or other base whereas approximately four molecular equivalentsare required for the hydrolysis of the diaeyloxy (3,12- diacyloxy)steroids specified herein. The hydrolysis is preferably conducted in anorganic solvent such as dioxane, methanol, and the like, and the productcan be recovered by concentration of the solution, acidification withdilute hydrochloric or other acid and filtration, or by extraction ofthe aqueous reaction mixture with ether or other water-immisciblesolvent.

Typical processes for producing typical compounds of this invention aredescribed in the examples which follow. It is to be understood thatthese are merely illustrative and are not to be construed as limiting.

Example 1.Maleic anhydride adduct 0] 3fi-acetoxy-12- hydr0xy-5,7,9 (11)-pregnatrien-20-0ne To a solution of 1.5 grams of the maleic anhydrideadduct of 3p-acetoxy-12-bromo-5,7,9(11)-pregnatrien-20- one (meltingpoint, 216-218 degrees centigrade; prepared as described in ourcopending application Serial No. 184,702, now U. S. Patent 2,623,043,issued December 23, 1952) in 150 milliliters of acetone was added sixtymilliliters of 0.1-normal silver nitrate solution. The addition was madeportion-wise with shaking. After one hour at room temperature, thesilver bromide which formed was removed by filtration and the filtratediluted with water until crystallization began. The product, filteredafter cooling, was 1.2 grams of 3B-acetoxy-12-hydroxy-5,7,9(11)-pregnatrien-20-one maleic anhydride adduct, meltingpoint 225-234 degrees centigrade. A sample recrystallized for analysismelted at 234-237 degrees centigrade. [111 plus 126.6 degrees(chloroform).

Analysis.Calculated for C27H32O'z: C, 69.21; H, 6.89. Found: C, 69.84;H, 7.02.

Example 2.Dimethyl maleate adduct 0 3,8-acet0xy-12- hydr0xy-5,7,9 1 1)-pregnatrien-2 0-0ne Similarly, by the method of Example 1, thecorresponding 12-brorno dimethyl maleate adduct (melting point,207.5-211 degrees centigrade; prepared as described in our copendingapplication Serial No. 184,702, now U. S. Patent 2,623,043, issuedDecember 23, 1952) hereinbefore was converted to3fl-acetoxy-12-hydroxy-5,7,9(1l) pregnatrien-ZO-one dimethyl maleateadduct, melting point 205-214 degrees centigrade. [411 plus at 139.6degrees (chloroform).

Analysis.Calculated for CzsHaeOe: C, 67.68; H, 7.44. Found:: C, 67.70;H, 7.48.

PREPARATION 1.MALEIC ANHYDRIDE ADDUCT 0F 318,12- DIACETOXY-5,7,9( 1 l)-PaEoNA'rn1Ez-I-20-oNts One half (05) gram of the maleic anhydrideadduct of 3 3 acetoxy l2 bromo 5,7,9(1l) pregnatrien 20- one (meltingpoint, 216-218 degrees centigrade; prepared as described in ourcopending application Serial No. 184,702), 0.5 gram of sodium acetate(dried for one hour at degrees centigrade), and 25 milliliters of aceticacid were mixed and heated at reflux for one hour. The acetic acid wasremoved in vacuo and the residue taken up in methylene chloride andwater. The methylene chloride layer was separated, washed with water anddried. Twenty-five (25) milliliters of isopropyl ether was added and thesolution concentrated until all of the methylene chloride was removed.Upon cooling, 0.27 gram of 3fi,12-diacetoxy-5,7,9(1l)-pregnatrien-20-onemaleic anhydride adduct, melting point 232-245 degrees centigrade,crystallized; the crystals were filtered from the solution. Severalrecrystallizations from acetonewater raised the melting point to 248-250degrees centigrade. [rtl plus 256 degrees (chloroform).

Analysis.-Calculated for C29H34Os: C, 68.21; H, 6.71. Found: C, 67.65;H, 6.55.

PREPARATION 2.-DIMETHYL MALEA'I'E ADDUCT 0F 3 3,12- DrAcaToxY-5 ,7 ,911)-PREGNATRIEN-20-ONE A solution of 2.7 grams. of the dimethyl maleateadduct of 3fi-acetoxy-12-bromo-5,7,9(11)-pregnatrien 20 one (meltingpoint, 207:5-211 degrees centigrade; prepared as described in ourcopending application Serial No. 184,702, now U. S. Patent 2,623,043,issued December 23, 1952) in 100 milliliters of acetic acid was warmedon the steam bath. Ten (10) grams of zinc dust was then addedportionwise to the warm solution over a period of ten minutes and themixture was heated for an additional hour. The zinc dust was removed byfiltration while the mixture was still hot and the filtrate diluted withone liter of water. The product, 35,12-diacetoxy-5,7,9(l1)-pregnatrien-20-one dimethyl maleate adduct, precipitated andwas collected by filtration. The yield was 1.98 grams; its melting pointwas 202-210 degrees centigrade, but it was raised on recrystallizationto 216- 218 degrees centigrade. [M plus 270.42 degrees (chloroform).

Analysis.--Calculated for CzrH42Oa: C, 66.64; H, 7.58; Elsi-1:230,15.41. Found: C, 66.57; H, 7.25; Cl-IsCO,

The same compound was obtained by treating 35,12- diacetoxy-5,7,9(11)-pregnatrien-20-one maleic anhydride adduct (Preparation 1) withdiazomethane.

Example 3.-Maleic acid adduct 319,12-dihydroxy- 5,7 ,9(] 1)-pregnatrien-20-one To a solution of 1.0 gram of the dimethyl maleateadduct of 3,l2-diacetoxy-5,7,9(11)-pregnatrien-20-one in 45 millilitersof dioxane was added an aqueous solution of 2.5 grams of sodiumhydroxide and the mixture was allowed to stand at room temperature forone hour. Twenty (20) milliliters of water was then added and themixture was allowed to stand an additional forty minutes. The reactionproduct was drowned out with water, extracted with ether and the etherextract washed, dried and evaporated to dryness. This yielded 426milligrams of the maleic acid adduct of 3fi,l2-dihydroxy-5,'7,9(11)-pregnatrien-ZO-one, which was not crystallized.

Example 4.Dimethyl maleate adduct of SfiJZ-a'ihydroxy-S ,7 ,9 (1 1)-pregnatrien-20-0ne The maleic acid adduct of 3,12-dihydroxy-5,7,9(1l)-pregnatrien-ZO-one obtained in Example 3 (0.426 gram) was dissolved inforty milliliters of a mixture of ether and methylene chloride (5:3) andthe solution was cooled in an ice bath. Ten milliliters of a solution ofdiazomethane in methylene chloride (equivalent to a stoichiometricexcessof diazomethahe) was added and the mixture was allowed to stand in thecold for thirty minutes and at room temperature forthirty minutes. Thesolution was then evaporated to dryness and the residue Was purified bychromatography over alumina. The fraction eluted from the chromatogramwith benzene-methanol (96:4) was crystallized from acetone-isopropylether and gave the dimethyl maleate adduct of 3fi,12-dihydroxy-5,7,9(l1)-pregnatrien-20-one, melting point 207-210 degrees centigrade.One recrystallization from the same solvlent raised its melting point to209-211 degrees centigra e.

Analysis.-Calculated for C27HssO1: C, 68.62; H, 7.68. Found: C, 68.67;H, 7.67.

Example 5.--Maleic acid and dimethyl maleate adducts of3p,12-dihydroxy-5,7,9 (1 1 -pregnatrien-20-one The dimethyl maleateadduct of 3,8,12-dihydroxy- 5,7,9(11)-pregnatrien-20-one is alsoobtained when the maleic anhydride adduct of 3}8,l2-diacetoxy-5,7,9(l1)-pregnatrien-ZO-one (Preparation 1, melting point 248-250 degreescentigrade) is treated with sodium hydroxide as in Example 3 and theresulting maleic acid adduct is esterified with diazomethane' as inExample 4.

Example 6.Dimethyl maleate adduct of 35,12-dihydroxy-5,7,9 (1 1-pregnatrien-20-one The dimethyl maleate adduct of 35,12-dihydroxy-5,7,9(l1)-pregnatrien-20-one is also obtained when the dimethyl maleateadduct of 3-acetoxy-12-hydroxy-5,7,9- (ll)-pregnatrien-20-one (Example2, melting point 205-214 degrees centigrade) is hydrolyzed in a similarmanner with sodium hydroxide and reesterified with diazomethane as inExample 4.

Example 7.C0nversi0n 0f the maleic acid to the maleic anhydride adduct 03 8,12-dihydr0xy-5,7,9(11)-pregnatrien-ZO-one When the maleic acidadduct of 3,8,12-dihydroxy- 5,7,9(11)-pregnatrien-20-one (Example 3) isheated for ZO-ones, respectively, having double bonds at the 5(6),

7(8) and 9(11) positions and the formula:

CH CH2 YO- I wherein Y has the significance hereinbefore specified. Theremoval of the maleic acid or maleic anhydride radical is effected by apyrolysis reaction which consists essentially in heating the maleic acidor maleic anhydride adduct ot' the 3fi-acyloxy-l2-hydroxy, or the3fl,l2'dihydroxy-5,7,9(11)-pregnatrien-2u-one in the presence of anorganic amine at a temperature of approximately to approximately 225degrees centigrade, with or without the presence of an organic solvent,and thereafter isolating the product triene. It is not necessary toisolate the adducts from a reaction mixture in which they are formed inorder to efIect the removal of the adduct radical in accordance withsuch pyrolysis processes, since the entire reaction mixture or crudeproduct may be treated. The desired triene can be obtained in a highdegree of purity and in excellent yields.

Amines which can be used in this pyrolysis process include: secondaryaliphatic amines such as dimethylamine, dietnylamine, dipropylamine,dibutylamine, diamylamine, dioctylamine; tertiary aliphatic amines suchas trimethylamine, triamylamine, methyldioctylamiue, methyldtethylamine;secondary and tertiary cycloaliphatic amines such asN-methylcyclohexylarnine, N,N-dimethylcyclohexylamine,N,N-diethylcyclohexylamine; secondary and tertiary heterocyclic aminessuch as pyrrolidine, N-methylmorpholine, N-ethylpyrrolidine, morpholine,piperidine, N-methylpiperidme, 2-methylpiperidine,1,2-o1metnylpiperidme, 1,2,4-trimethylpiperrdine,2,4,6-trimethylpiperidine, 1-ethyl-2,4,6-trimethylpiperidine; aromaticheterocyclic amines such as pyridine, picoline, lutidine, collidine,quiholine, quinaloine, lepidine, B-methylquinoline; secondary andtertiary caroocyclic aromatic amines such as N-methylaniline,N-ethylanih'ne, N-butylaniline, N-benzylaniline, N,N-dimetnylani1ine,N,N-diethylaniline, N,N-dibutylanih'ne, N,N-dioenzylaniline,N-methyltoluidine, N,N-diethy1toluidine, N-etnylxylidine,N,N-dimethylxylidine; substituted aliphatic amines such asdiethylaminoethanol, dibutylaminoethanol, N-pyrrolidylethanol,N-piperidylethanol; substituted aromatic amines such asortho-methoxy-N,N-dimethylaniline, para-ethoxy N,N diethylanilme,para-chloro-N,N-dimethylaniline, para-bromo N,N diethylaniline,parafluoro-N,N-dibutylaniline, N,N-dimethylmesidine (N,N-dimethyl-2,4,6-trimethylaniline); secondary and tertiary aralkyl aminessuch as methylbenzylamine, dimethylbenzylamine, propylbenzylamine,diisopropylphenethylamine, diethylphenylisopropylamine; and primaryamines such as butylamine, hexylamine, octylamine, cyclohexylamine,aniline, toluidine, xylidine and the like.

The process comprises heating the selected 3B-acyloxy- 12-hydroxy or318,12-dihydroxy-5,7,9( l l )-pregnatrien- 20-one maleic acid or maleicanhydride adduct to a temperature between approximately 100 andapproximately 225 degrees centigrade, preferably between and 200 degreescentigrade, in the presence of an organic amine, removing excess amine,and recovering the product triene. The'time required for the reaction isusually from approximately one to approximately eight hours, dependingupon such factors as the particular steroid adduct being treated, theamine employed, and the temperature of reaction. Ordinarily, a reactionperiod of approximately four hours is entirely satisfactory, although,at lower temperatures, a more extended period may be employed worms toadvantage. The employment of pressure may in some cases be advantageous,although it .is inmost cases preferred to conduct the pyrolysis reactionat atmospheric pressure. After completion of the reaction, the puretriene product can be recovered in conventional manner, such as byevaporation 'of solvent in vacuo, redissolving the residue in an organic:solvent, e. g., methanol, diluting with water, extracting with ether,washing the solution until neutral, drying, evaporating to dryness,chromatographing over an alumina column, and recrystallizing from anorganic solvent, if desired.

Such processes, which are exemplified by the conversion of maleic acidand maleic anhydride adducts of other steriods of this series, are morefully disclosed in our copending application Serial No. 228,134, filedon May 24, 1951, now Patent No. 2,655,516.

Inasmuch as the foregoing specification comprises preferred embodimentsof our invention, it is to be understood that alterations andmodifications may be made therein in conventional manner and that theinvention is limited solely by the scope of the claims appended hereto.

We claim:

1. An adduct of a 12-hydroxy-5,7,9(1-1)-pregnatrien- 20-one :having theformula:

in which Y is a radical of the group consisting'of hydrogen andhydrocarbon acyl radicals containing .from one to eight carbon :atoms,inclusive, and A .is the adduct radical of an aye-unsaturated carbonylcompound of the group consisting of maleic vacid, maleic .anhydride, anddi-lower-alkyl maleates.

2. An adduct of a 3B,l2-dihydroxy-5,7,9.( 11)-pregnatrien-ZO-one and ana,p-.unsaturated carbonyl comin which Y is :a radical of \the vgroupconsisting .of hydrogen and acyl radicals containing from one to .eightcarbon atoms, inclusive, and A is the adduct radical of angs-unsaturated icarbonyl compound of the group consist-ing of maleicacid, maleic anhydride, and idi-lowerin which A and Y have thesignificance hereinbefore specified, "with a silver :salt, andsubsequent recovery of the resulting adduct of the 12-hydroxy-5,7,9(11)-pregnatrien-ZO-one.

9. A process ;for the production ,of an adduct of a3,6,12-dihydroxy:5,7,%(;1 l) -,pregnatrien-20- one having the formula:

CH: CH:

in which A is the ,adduct radicalof ianufi-unsaturated carbonyl compoundvof the group consisting of maleic acid, maleic vanhydride, anddi-lower-alkyl maleates, which comprises .thereaction .with a .base ofan adduct of va 12-acyloxy 5,7,9 (.1'1;)Tpregnatrien-ZO-one having theformula:

in=which X-is an aoyloxy radicalcontaining from one-to eightcarbonatoms, inclusive, and Y'is a radical of the group consisting ofhydrogen andacyl radicalscontaining from one ,toeight :carbon atomsinclusive, :and A is the adduct radical as specified hereinbefore,andsubsequentrecovery ,of the resultingadduct. ofthel3fi,12-dihydroxy-,5,7,9,(.11J)-pregnatrien 2j01one.

No references ,cited.

1. AN ADDUCT OF A 12-HYDROXY-5,7,9(11)-PREGNATRIEN20-ONE HAVING THEFORMULA: